It is known that glycine transporters inhibitors are suitable for the treatment of neurological and neuropsychiatric disorders. The majority of diseases states implicated are psychoses, schizophrenia (Armer R E and Miller D J, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001), psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders such as acute mania or depression, associated with bipolar disorders and mood disorders, associated with schizophrenia, (Pralong E T et al., Prog. Neurobiol., 67: 173-202, 2002), autistic disorders (Carlsson M L, J. Neural Trans., 105: 525-535, 1998), cognitive disorders such as dementias, including age related dementia and senile dementia of the Alzheimer type, memory disorders in a mammal, including a human, attention deficit disorders and pain (Armer R E and Miller D J, Exp. Opin. Ther. Patents, 11 (4): 563-572, 2001). Thus, increasing activation of NMDA receptors via GlyT-1 inhibition may lead to agents that treat psychosis, schizophrenia, dementia and other diseases in which cognitive processes are impaired, such as attention deficit disorders or Alzheimer's disease.
Although sickle cell disease and its clinical manifestations have been recognized within West Africa for several centuries, the first report of sickle cell disease appearing in the medical literature occurred only in 1910 by James B. Herrick.
Worldwide, it is believed that there are in excess of four million sickle cell disease patients today. The majority of them are in Africa, mostly in the Central and Western regions. About 100.000 patients, primary of African or Latin origin, live in the USA, another 100.000 are in Europe. The disease also affects four to five million people in the Middle East, India, South America and the Caribbean.
This hereditary condition is believed to have started in the Western and Central parts of Africa. In those areas, sickle cell trait or carrier status was beneficial because the single gene actually protected a person from malaria. As a result, those with the gene survived the malaria epidemic in the affected regions of Africa. However, people who inherited the affected gene from both parents, had the condition called sickle cell anemia.
Aside from sickle cell anemia, other genetic changes can result in similar conditions and are categorized under sickle cell disease. Sickle cell anemia is the most common type of the sickle cell disease. Other major conditions in the same category include: SC disease (a combination of sickle mutation and hemoglobin C mutation) and Sβ-thalassemia or Sα-thalassemia (a combination of sickle mutation and β-thalassemia mutation or α-thalassemia). In all of these conditions, patients can have severe painful episodes and organ damage.
Sickle cell anemia and the existence of sickle hemoglobin (Hb S) was the first genetic disease to be understood at the molecular level. It is recognized today as a morphological and clinical result of a glycine to valine substitution at the 6 position of the beta globin chain. The major source of morbidity and mortality of patients suffering from sickle cell disease is vascular occlusion caused by sickle cells, which causes repeated episodes of pain in both acute and chronic form and causes also ongoing organ damage with the passage of time.
The deformation and distortion of sickle cell erythrocytes upon complete de-oxygenation is caused by polymerization and intracellular gelation of sickle hemoglobin S. The intracellular gelatin and polymerization of Hb S can occur at any time during erythrocyte's journey through the vasculature. Thus, erythrocytes in patients with sickle cell disease containing no polymerized hemoglobin S may pass through the microcirculation and return to the lungs without sickling, but may sickle in the veins or may sickle in the capillaries. For red cells that sickle within the capillaries, a number of possible consequent events exist, ranging from no effect on transit time, to transmit occlusion of the capillary, to a more permanent blockage that may ultimately result in ischemia or infarction of the surrounding cells, and in the destruction of the red cell. When the blood vessels are blocked, oxygen and nutrients cannot be carried to the area covered by the affected blood vessels and tissue in the area will die and cause severe inflammation and heart attacks. This happens not just once or twice, but closer to several times a year.
Today, there are limited measures for treating sickle cell disease. The use of antibiotics over the last 50 years has done much to prevent deadly infection among children with this disease, leading to major improvements in survival rates in developed countries. The only cure for sickle cell disease is stem cell transplantation; however, this is available to a very limited number of patients due to scarcity of matched donors.
Since the mid 90's, an oral medication called hydroxyurea has been available for prevention of “painful crises”. For those who can take this medication on a regular basis, it has improved their quality life immensely. However, it is a medicine that was originally designed for certain types of cancer and has many side effects, including suppression of white blood cells that fight infection, skin ulcers, stomach problems and anemia.